OA12893A - Broadspectrum 2-Amino-Benzothiazole Sulfonamide HIV Protease Inhibitors. - Google Patents

Abstract

The present invention relates to the use of 2-amino-benzothiazoles, having the formula (I) wherein R1 is hexahydrofuro[2,3-b]furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or phenyl optionally substituted with one or more substituents independently selected from C1-6-alkyl, hydroxy, amino, halogen, aminoC1-4-alkyl and mono-or di(C1-4alkyl)amino; R2 is hydrogen or C1-6alkyl; L is a direct bond, -0-, C1-6 alkanediyl-O- or -O-C1-6alkanediyl; R3 is phenylC1-4alkyl; R4 is C1-6alkyl; R5 is hydrogen or C1-6alkyl; R6 is hydrogen or C1-6alkyl; in the manufacture of a medicament useful for inhibiting mutant HIV protease in a mammal infected with said mutant HIV protease. It also relates to novel compounds of formula (I).

Description

012893 -1-

BROADSPECTRUM 2-AMTNO-BENZQTHIAZOLE SULFONAMIDE HIV

PROTEASE INHIBITORS

This application daims priority benefît to EP Application EP 02078231.4 filed onAugust 2,2002 and to U.S. Provisional Application No. 60/427,862, filed onNovember 20,2002, tbe contents of which are expressly incorporated by referenceherein.

The présent invention relates to 2-amino-benzothiazole sulfonamides, their use asbroadspectrum HIV protease inhibitors, processes for their préparation as well aspharmaceutical compositions and diagnostic kits comprising them. The présentinvention also concems combinations of the présent 2-aminobenzoxazoIe sulfonamideswith another anti-retroviral agent. It further relates to their use in assays as referenceconrpounds or as reagents.

The virus causing the acquïred immunodeficiency syndrome (AIDS) is known bydifferent names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) or AlDS-related virus (ARV) or human immunodeficiencyvirus (HIV). Up until now, two distinct fatnilies hâve been identified, i.e. HIV-1 andHIV-2. Hereinafter, HIV will be used to generically dénote these viruses.

One of the critical pathways in a retroviral life cycle is the processing of polyproteinprecursors by aspartic protease, For instance, with the HIV virus the gag-pol protein isprocessed by HIV protease. The correct processing of the precursor polyproteins bythe aspartic protease is required for the assembly of infectious virions, thus making theaspartic protease an attractive target for antiviral therapy. In particular for HIVtreatment, the HIV protease is an attractive target. HIV protease inhibitors (Pis) are commonly administered to AIDS patients incombination with other anti-HIV compounds such as, for instance nucleoside reversetranscriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs), nucléotide reverse transcriptase inhibitors (NtRTIs) or other proteaseinhibitors. Despite the fact that these antiretrovirals are very useful, they hâve acommon limitation, namely, the targeted enzymes in the HIV virus are able to mutatein such a way that the known drugs become less effective, or even ineffective againstthese mutant HIV viruses. Or, in other words, the HIV virus créâtes an ever-increasingrésistance against the available drugs. -2-

Resistance of retroviruses, and in particular the HIV virus, against inhibitors is a majorcause of therapy failure. For instance, half of the patients receiving anti-HIVcombination therapy do not respond fiilly to the treatment, mainly because of résistanceof the virus to one or more drugs used. Moreover, it has been shown that résistant virusis carried over to newly infected individuals, resuîting in severely limited therapyoptions for these drug-naive patients. On the International AIDS Conférence in Paris inJuly 2003 researchers relèased that the biggest study so far of résistance to AIDS drugsfinds that about 10 percent of ail newly infected people in Europe hâve drug-resistantstrains. Smaller tests to détermine the spread of résistance hâve been done in the high-risk city center of San Francisco. This test sbowed the highest level of résistance at 27percent. Therefore, there is a need in the art for new compounds for retrovirus therapy,more particularly for AIDS therapy. The need in the art is particularly acute forcompounds that are active not only on wild type HIV virus, but also on the increasinglymore common résistant HIV viruses.

Known antiretrovirals, often administered in a combination therapy regimen, willeventually cause résistance as stated above. This often may force the physician toboost the plasma levels of the active drugs in order for said antiretrovirals to regaineffectivity against the mutated HTV viruses. The conséquence of which is a highlyundesirable increase in pill burden. Boosting plasma levels may also lead to anincreased risk of non-compliance with the prescribed therapy. Thus, it is not onlyimportant to hâve compounds showing activity for a wide range of HIV mutants, it isalso important that there is little or no variance in the ratio between activity againstmutant HIV virus and activity against wild type HIV virus (also defined as foldrésistance or FR) over a broad range of mutant HIV strains. As such, a patient mayremain on the same combination therapy regimen for a longer period of time since thechance that a mutant HIV virus will be sensitive to the active ingrédients will beincreased.

Finding compounds with a high potency on the wild type and on a wide variety ofmutants is also of importance since the pill burden can be reduced if therapeutic levelsare kept to a minimum. One additional way of reducing this pill burden is finding anti-HIV compounds with good bioavailability, i.e. a favorable pharmacokinetic andmetabolic profile, such that the daily dose can be minimized and consequently also thenumber of pills to be taken.

Another favorable characteristic of an anti-HIV compound is that plasma proteinbinding of the inhibitor has minimal or even no effect on its potency. 012893 -3-

Thus, there is a high medical need for protease inhibitors that are able to combat abroad spectrum of mutants of the HIV virus with little variance in fold résistance.

Those protease inhibitors with a good bioavailability and little or no effect on their potency due to plasma protein binding hâve additional advantages. 5

Up until now, several protease inhibitors are on the market or are being developed.

One particular core structure (depicted below) has been disclosed in a number ofréférencés, such as, WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. The compounds disclosed therein are 10 described as retroviral protease inhibitors.

WO 99/67254 discloses 4-substituted-phenyl sulfonamides capable of inhibiting multi-drug résistant retroviral proteases.

15 Surprisingly, the 2-amino-benzothiazole sulfonamides of the présent invention arefound to hâve a favorable virological profile. Not only are they active against wild-type HIV virus, but they also show a broadspectrum activity against various mutantHIV viruses exhibiting résistance against known protease inhibitors. 20 The présent invention concems the use of 2-amino-benzothiazole protease inhibitors,having the formula

and /V-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters andmétabolites thereof, wherein 25 R| is hexahydrofuro[2,3-b]furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, orphenyl optionally substituted with one or more substituents independently -4- selected from Ci.6alkyl, hydroxy, amino, halogen, aminoCi^alkyl and mono-ordi(C i -4alky l)amino ; R2is hydrogen or Ci-ealkyl; .Lis a direct bond,-O-, Ci-salkanediyl-O-or-O-Ci.6alkanediyl; R3 is phenylCiutalkyl;

Riis Ci^alkyl; R5 is hydrogen or Ci-ealkyl;

Rg is hydrogen or Cj^alkyl; in the manufacture of a médicament useful for inhibiting mutant HIV protease in amammal infected with said mutant HIV protease. Said mammal in particular is abuman being. The compounds of the présent invention are in particular useful in themanufacture of a médicament useful for inhibiting a broad range of mutant HIVproteases. ' A spécial interest goes to the free base, sait or N-oxidc form of the compounds offormula (I), and their stéréo isomeric foims.

Also of spécial interest is the use of the présent compounds wherein Ri is tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or phenyl optionally substituted withone or more substituents independently selected from Cj^alkyl, hydroxy, amino,halogen, aminoCMalkyl and mono-or di(Ci4alkyl)ammo in the manufacture of amédicament useful for inhibiting mutant HIV protease in a mammal infected with saidmutant HIV protease. A mutant of the HIV protease enzyme is defîned as an HIV protease enzyme which hasat least one mutation in its amino acid seqüence relative to the amino acid sequence ofthe wild-type HIV protease. For purposes of denoting the mutants throughout the text,the IIXB2 wild type rcfcrcnce (HIV IIIB LAI wild type), of which the sequence can befound atNIH’s GenBank, is used.

The standard of “sensitivity” or alternatively “résistance” of a HIV protease enzyme to adrug is set by the commercially available HIV protease inhibitors. As explainedhereinabove, existing commercial HIV protease inhibitors may loose effectivity overtime against a population of HIV virus in a patient. The reason being that underpressure of the presence of a particular HIV protease inhibitor, the existing populationofHIV virus, often mainly wild type HIV protease enzyme, mutâtes into differentmutants which may be less sensitive to that same HIV protease inhibitor. If thisphenomenon occurs, one talks about résistant mutants. If those mutants are not only 012893 -5- resistantto that one particular HIV protease inhibitor, but also to one or multiple othercommercially available HIV protease inhibitors, one talks about multi-drug résistantHIV protease. One way of expressing the résistance of a mutant to a particular HIVprotease inhibitor is making the ratio between the EC50 of said HIV protease inhibitoragainst mutant HIV protease over EC50 of said HŒV protease inhibitor against wild typeHIV protease. Said ratio is also called fold résistance (FR). .

Many of thé mutants occurring in the clinic hâve a fold résistance of 100 or moreagainst the commercially available HIV protease inhibitors, like saquinavir, indinavir,ritonavir and nelfmavir. Clinically relevant mutants of the HTV protease enzyme can forinstance be characterized by a mutation at amino acid position 10, 71 and/or 84.Examples of such clinical relevant mutant HIV proteases are listed in Table 1.

The compounds ofthe présent invention show a fold résistance ranging between 0.01and 100 against at least one, often against a broad range, of clinically relevant mutantHIV proteases. A particular group of compounds of formula (I) are those compounds offormula (I) showing a fold résistance against at least one mutant HIV protease rangingbetween 0.1 and 100, suitably ranging between 0.1 and 50, and more suitably rangingbetween 0.1 and 30, Of particular interest are the compounds of formula (I) showing afold. résistance against at least one mutant HIV protease ranging between 0.1 and 20,and even more interesting are those compounds of formula (Γ) showing a fold résistanceagainst at least one mutant HIV protease ranging between 0.1 and 10.

Thus, the présent invention relates to the use of a compound of formula (I) in themanufacture of a médicament useful for inhibiting réplication of a HIV virus having amutant HIV protease, in particular a multi-drug résistant mutant HIV protease. It alsorelates to the use of a compound of formula (I) in the manufacture of a médicamentuseful for treating or combating a disease associated with HTV viral infection whereinthe protease of the HIV virus is mutant, in particular a multi-drug résistant mutant HTVprotease.

In other words, the présent invention relates to a method of inhibiting a mutant HIVprotease, in particular a multi-drug résistant mutant HIV protease, in a mammalinfected with said mutant HIV protease, said method comprising contacting said mutantHIV protease in said mammal with an effective amount of a compound of formula (I).The présent invention also relates to a method of inhibiting réplication of a HIV virus,which has a mutant HIV protease, in particular a multi-drug résistant mutant HIVprotease, in a mammal, said method comprising contacting said HTV virus, which has amutant HIV protease, in said mammal with an effective amount of a compound of 012893 -6- formula (I). The présent invention further relates to a method of treating or combatinga mammalian disease associated with HIV viral infection wherein the protease of theHIV virus is mutant, in particular a multi-drug résistant mutant HTV protease, saidmethod comprising contacting said HIV virus wherein the protease of the HIV virus ismutant infecting said mammal with an effective amount of a compound of formula (I).

Of particular interest is that the compounds of the présent invention can be used in themanufacture of a médicament for the treatment of individuals infected with mutant HIVprotease bearing a mutation at least at one of the amino acid positions 10, 71 or 84 or atleast a combination of two of these positions or at least a combination of ail three. A basic nitrogen occurring in the présent compounds can be quatemized with any agentknown to those of ordinary skill in the art including, for instance, lower alkyl halides,dialkyl sulfates, long chain halides and aralkyl halides.

Whenever the terra “substituted” is used in defîning the compounds of formula (I), it ismeant to indicate that one or more hydrogens on the atom(s) indicated in the expressionusing “substituted” is replaced with a sélection from the indicated group, provided thatthe indicated atorn’s normal valency is not exceeded, and that the substitution results ina chemically stable compound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, and formulation into atherapeutic agent.

As used herein, the term “halo” or “halogen” as a group or part of a group is generic forfluoro, chloro, bromo or iodo.

The terra “Ci^alkyl” as a group or part of a group defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, forexample, methyl, ethyl, propyl, butyl and 2-methyl-propyl.

The term “Ci.6alkyl” as a group or part of a group defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as thegroups defined for Ci^alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and thelike.

The term “Cualkanediyl” as a group or part of a group defines bivalent straight andbranched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms suchas, for example, methylene, ethan-l,2-diyl, propan-l,3-diyl, propan-l,2-diyl,butan-l,4-diyl, pentan-l,5-diyl, hexan-l,6-diyl, 2-methylbutan-l,4-diyl, 3-methyI-pentan-l,5-diyl and the like. 012893 -7-

As used herein, the terni “one or more” covers the possibility of ail the available atoms,where appropriate, to be substituted, preferably, one, two orthree.

The term “prodrug” as used throughout this text means the pharmacologicallyacceptable dérivatives such as esters, amides and phosphates, such that the resulting invivo biotransformation product of the dérivative is the active drug as defined in thecompounds of formula (I). The reference by Goodman and Gilman (The Pharmaco-logical Basis of Therapeutics, ed, McGraw-Hill, Int. Ed. 1992, “Biotransformationof Drugs”, p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs ofa compound of the présent invention are prepared by modifying functional groupsprésent in the compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugs include compoundsof the présent invention wherein a hydroxy group, for instance the hydroxy group ontire asymmetric carbon atom, or an amino group is bonded to any group that, when theprodrug is administered to a patient, cleaves to fonn a free hydroxyl or free amino,respectively.

Typical examples of prodrugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 ail incorporated herein by reference.

Prodrugs are typically characterized by excellent aqueous solubility, increasedbioavailability and are readily metabolized into the active inhibitors in vivo.

For therapeutic use, the salts of the compounds of formula (I) are those wherein thecounterion is pharmaceutically or physiologically acceptable. However, salts having apharmaceutically unacceptable counterion may also fmd use, for example, in thepréparation or purification of a pharmaceutically acceptable compound of formula (I).Ail salts, whether pharmaceutically acceptable or not are included within the ambit ofthe présent invention.

The pharmaceutically acceptable or physiologically tolerable addition sait forms whichthe compounds of the présent invention are able to form can conveniently be preparedusing the appropriate acids, such as, for example, inorganic acids such as hydrohalicacids, e.g. hydrochloric or hydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoricand the like acids; or organic acids such as, for example, acetic, aspartic,dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic,pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methane-sulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. 012893 -8-

Conversely said acid addition sait forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also be converted intotheir non-toxic métal or amine addition sait form by treatment with appropriate organicand inorganic bases. Appropriate base sait forms comprise, for example, theammonium salts, the alkali and earth alkaline métal salts, e.g, the lithium, sodium,potassium, magnésium, calcium salts and the like. salts with organic bases, e.g. thebenzathine, N-methyl, -D-glucamine, hydrabamine salts, and salts with amino acidssuch as, for example, arginine, lysine and the like.

Conversely said base addition sait forms can be converted by treatment with anappropriate acid into the free acid form.

The terni “salts” also comprises the hydrates and the solvent addition forms that thecompounds of the présent invention are able to form. Examples of such forms are e.g.hydrates, alcoholates and the like.

The TV-oxide forms of the présent compounds are meant to comprise the compounds offormula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide.

The présent compounds may also exist in their tautomeric forms. Such forms, althoughnot explicitly indicated iri the above formula are intended to be included within thescope of the présent invention.

The terril stereochemically isomeric forms of compounds of the présent invention, asused hereinbefore, defines ail possible compounds made up of the same atoms bondedby the same sequence of bonds but having different three-dimensional structures whichare not interchangeable, which the compounds of the présent invention may possess.Unless otherwise mentioned or indicated, the Chemical désignation of a compoundencompasses the mixture of ail possible stereochemically isomeric forms that saidcompound might possess. Said mixture may contain ail diastereomers andTorenantiomers of the basic molecular structure of said compound. Ail stereochemicallyisomeric forms of the compounds of the présent invention both in pure form and inadmixture with each other are intended to be embraced within the scope of the présentinvention. -9-

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein aredefined as isomers substantially fr.ee of other enantiomeric or diastereomeric forms of thesaine basic molecular structure of said compounds or intermediates. In particular, theterra 'stereoisomerically pure’ concems compounds or intermediates having astereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum10% of the other possible isomers) up to a stereoisomeric excess of 100% (Le. 100% ofone isomer and none of the other). more in particular, compounds or intermediates havinga stereoisomeric excess of 90% up to 100%, even more in particular having astereoisomeric excess of 94% up to 100% and most in particular having a stereoisomericexcess of97%up to 100%. The tenus 'enantiomerically pure' and ’diastereomericallypure' should be understood in a similar way, but then having regard to the enantiomericexcess, respectively the diastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention maybe obtained by the application of art-known procedures. For instance, enantiomers maybe separated ffom each other by the sélective crystallization of their diastereomericsalts with optically active acids or bases. Examples thereof are tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Altematively,enantiomers may be separated by chromatographie techniques using chiral stationaryphases. Said pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriate startingmaterials, provided that the reaction occurs stereospecifically. Preferably, if a spécifiestereoisomer is desired, said compound would be synthesized by stereospecificmethods of préparation. These methods will advantageously employ enantiomericallypure starting materials.

The diastereomeric racemates of formula (I) can be obtained separately by conventionalmethods. Appropriate physical séparation methods that may advantageously beemployed are, for example, sélective crystallization and chromatography, e.g. coluinnchromatography.

It is clear to a person skilled in the art that the compounds of formula (I) contain at leasttwo asymmetric centers and thus may exist as different stereoisomeric forms. Thesetwo asymmetric centers are indicated with an asterisk (*) in the figure below.

OR3 O

012893 -10-

The absolute configuration of eacb asymmetric center that may be présent in thecompounds of formula (I) may be indicated by the stereochetnical descriptors R and S,this R and S notation corresponding to the raies described in Pure Appl. Chem. 1976,45, 11-30. The carbon atom bearing the hydroxy group and marked with the asterisk(*) preferably has the R configuration. The carbon atom bearing the R3 group andmarked with the asterisk (*) preferably has the S configuration.

The présent invention is also intended to include ail isotopes of atoms occurring on theprésent compounds. Isotopes include those atoms having the same atomic number butdifferent mass numbers. By way of general example and without limitation, isotopes ofhydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Whenever used hereinafter, the term “compounds of formula (I)”, or “the présentcompounds” or similar term is meant to include the compounds of general formula (1),their TV-oxides, salts, stereoisomeric fonns, racemic mixtures, prodrugs, esters andmétabolites, as well as their quatemized nitrogen analogues.

Some of the compounds of formula (I) hâve been disclosed in WO 95/06030, i.e.{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropylj-carbamic acid benzyl ester; {( 1 S,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobuty 1-amino]-1 -benzyl-2-hydroxypropyl}-carbamic acid pyridin-3-ylmethyI ester;{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyî-2-hydroxypropyl}-carbamic acid thiazol-5-ylmethyl ester;{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfony])-isobutyl-aniino]-l-benzyl-2-hydiOxypropyl}-2-(2,6-dimethyi-phenoxy)-acetamide; 3- amino-{(lS,2R)-3-I(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-2-methyl-bcnzamide; 4- amino-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-î-benzyî-2-hydroxypiOpyl}-2-methyl-benzamide; 5- amino-{(lS,2R)-3-[(2-amino~benzothÎazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-2-methyl-benzamide; N-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2- hydroxypropyl}-2-methyl-benzamide; N-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2- hydroxypropyl}-4-hydroxy-2-methyl-benzamide; N-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyI)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-3-hydroxy-2-methyl-benzamide; and 012893 -11- {(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid (S)-(tetrahydrofuran-3-yl) ester.

Hen.ce, the présent invention also concerns the compounds of formula (I)

O. R3 O

and JV-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters andmétabolites thereof, wherein

Ri is hexahydrofuro[2,3-b]faranyl, tetrahydroftiranyl, oxazolyl, thiazolyl, pyridinyl., orphenyl optionally substituted with one or more substitueras independentlyselected from Ci-6alkyl, hydroxy, amino, halogen, aminoCMalkyl and mono-ordi(C i-4alkyl)amino;

Rais hydrogenorCi^allcyl; L is a direct bond, -O-, Ci^alkanediyl-O- or -O-Ci_6alkanediyl;

Ra is phenylCmalkyl;

Rus Cj-galkyl; R5 is hydrogen or Ci^alkyl; Rôis hydrogen or Ci-galkyl; provided that the compounds are other tiian : {(1 S,2R)-3-[(2-ammo-benzothiazole-6-sulfonyl)-isobutyl-amino]-1 -benzyl-2-hydroxypropyl}-carbamic acid benzyl ester; {( 1S ,2R)-3- [(2 -amino-benzothiazote- 6 -sulfonyl)-isobutyl-amino] -1 -benzyl-2-hydroxypropyl} -carbamic acid pyridin-3-ylmetbyl ester;{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-ainino]-l-benzyl-2-hydroxypropyl)-carbamic acid thiazol-5-ylmethyl ester; {(1 S,2R)-3- [(2-aroino-benzothiazole-6-sulfonyl)-i sobutyl-amino] -1 -benzyl-2-hydroxypropyl}-2-(2,6-dimethyl-phenoxy)-acetamide; 3- amino-{QS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl} -2-methyl-benzamide; 4- amino-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl} -2-methyl-benzamide; 5- amino- {(1 S,2R)-3-[(2-ammo-benzothiazole-6-sulfonyl)-isobutyl-amino]-1 -benzyl-2-hydroxypropy 1} -2-methyl-benzamide; N- {(1 S,2R)-3-[(2-amÎno-benzothiazole-6-sulfonyl)-isobutyl-amino]-1 -benzyl-2-hydroxypropyl}-2-methyl-benzamide; 012893 -12- N-{(1 S,2R)-3-[(2-amino-benzothiazole-6-suIfonyl)-isobutyl-amino]-l -benzyl-2-hydroxypropyl} -4-hydroxy-2-methyl-benzamide; N-{(lS,2R)-3-[(2-amino-benzothiazole-fosulfonyl)-isobutyl-aniino]-l-benzyl-2-hydroxypropyl}-3-hydroxy-2-methyl-benzamide; and{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid (S)-(tetrahydrofuran-3-yl) ester.

Interesting compounds are those compounds of formula (I) wherein R1 is hexahydrofuro[2,3-b]furanyl or oxazolyl.

Other interesting compounds are those compounds of formula (I) or those compoundsbelonging to any subgroup thereof wherein Ri is hexahydroforo[2,3-b]furariyl,tetrahydrofiiranyl, oxazolyl, thiazolyl, and L is a direct bond.

Yet other interesting compounds are those compounds of formula (I) or thosecompounds belonging to any subgroup thereof wherein R] is hexahydrofuro[2,3-b] fur any 1, oxazolyl, thiazolyl, pyridinyl, or phenyl optionally substïtuted with one ormore substituents independently selected from Ci-ealkyl, hydroxy, amino, halogen,aminoCi^alkyl and mono-or di(CMalkyl)amino; and L is -O-.

Still other interesting compounds are those compounds of formula (I) or thosecompounds belonging to any subgroup thereof wherein Ri is hexahydrofuro[2,3-bjforanyl, tetrahydrofuranyl, oxazolyl, or phenyl substïtuted with one or moresubstituents independently selected from Ci^alkyl, hydroxy, amino, halogen, aminoC[.4alkyl and mono-or di(C i-4aIkyi)amino; and L is C[-ôalkanediyl-O- whereby the -O- isattached to the nitrogen of the amide.

Also interesting compounds are those compounds of formula (I) or those compoundsbelonging to any subgroup thereof wherein Ri is hexahydrofuiO[2,3-b3furanyl,tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or phenyl optionally substïtuted withone or more substituents independently selected from hydroxy, amino, halogen,aminoCi^alkyl and mono-or di(Cualkyl)amino; and L is -O-Ci.6alkanediyl whereby -O- is attached to the R1 group. A suitable group of compounds are those compounds of formula (I) or those compoundsbelonging to any subgroup thereof wherein at least one of R5 and R6 is Ci-ealkyl, inparticular R5 is methyl and Rg is hydrogen or methyl, more in particular R5 is methyland Ré is hydrogen. 012893 -13-

Compounds of particular interest are those compounds of formula (I) or thosecompounds belonging to any subgroup thereof wherein -L-R1 is -O-(hexahydrofuro[2,3-bjfuranyl), -O-tetrabydrofuranyl. -O-methyl-(optionaIly substituted phenyl), -O-methyl-pyridinyl, -O-methyl-thiazolyl, -O-methyl-oxazolyl, -methyl-O-(optionally substitutedphenyi) or optionally substituted phenyl. Preferably, the optional substituents on thephenyi group are methyl, amino, hydroxy, halogen, aminomethyl,

Compounds of spécial interest are those compounds of formula (I) or those compoundsbelonging to any siibgroup thereof wherein R* is hexahydrofuro[2,3-b]furanyl,tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or phenyl optionally substituted withone or more substituents independently selected front Ci-salkyl, hydroxy, amino,chloro, bromo, aminoCi^alkyl and mono-or di(Ci.4.alkyl)amino.

Suitably, one or more of the following restrictions apply to any of the above mentionedinteresting subgroups of the compounds of formula (I) or subgroups of particular orspécial interest: R2 is hydrogen; R3 is phenylmethyl; R4 is C ualkyl, preferably isobutyl; R5 is hydrogen or methyl; R6 is hydrogen or methyl.

An interesting combination for a compound of formula (Γ) or a compound of anysubgroup thereof is formed by R2 being hydrogen; R3 beïng phenylmethyl and R4 beingCi^alkyl, preferably isobutyl; A spécial subgroup of the compounds of formula (I) is defmed as encompassing thosecompounds of formula (I) wherein R5 and Rfi are both hydrogen.

Another spécial subgroup ofthe compounds of formula (1) or ofthe compoundsbelonging to any subgroup thereof are those compounds wherein -L-R* is-O-(hexahydrofuro[2,3-b]furanyl), -O-tetrahydrofuranyl, -O-methyl-thiazolyl, -O-methyl-oxazolyl, -methyl-O-(2,6-dimethylphenyl), -methyl-O-(4-aminomethyl-2,6-dimethylphenyl), -methyl-O-(4-amino-2,6-dimethylphenyl), 3-hydroxy-2-methyl-phenylor 3-amino-2-methyl-phenyl; and R3 is methyl or hydrogen and R6 is hydrogen.

Preferred compounds are 012893 -14- {3-[(2-ammo-benzothiazole-6-sulfonyl)-isobutyl-annno]-l-benzyl-2-hydroxypropyl}-carbamic acid hexahydro-furo[253-b]furan-3-yl ester; { 3 -[(2 -ammo-benzothiazole-6-sulfonyl)-isobutyl-amino} -1 -benzyl-2-hy droxypropyl} -carbamic acid thiazol-5-yhnethyI ester; {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-aniino]-propyl) -carbamic acid hexahydro-ftiro[2,3-b]iuran-3-yl ester; {l-benzyl-3-[(2-dimethylamino-benzothÎazole-6-sulfonyl)-isobutyl-ainino]-2-hydiOxy-propyl}-carbamic acidhexahydro-furo[253-b]furan-3-yl ester;{3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbatnic acid benzyl ester; N-{3-[(2-amino-benzothiazoIe-6-sulfonyl)-isobutyl-aniino]-l-benzyl-2- hy droxypropyl} -2-(2,6-dimethyl-phenoxy)-acetami de; {3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzÿl-2-hydiOxypropyl}-carbamic acid pyridin-3-ylmethyl ester; 3-amino-N-{3-[(2-araino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hy droxypropyl} -2-methyl-benzamide; N- {3 - [(2-amino-benzothiazole-6-sulfony l)-isobuty 1-amino] -1 -benzyl-2 - hydroxypropyl}-3'hydroxy-2-methyl-benzamide; {3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid tetrahydro-fiiran-3-yl ester; N- {3 - [(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino J -1 -benzyl-2 - hydiOxypropyl}-2~methyl-benzamide; N-{l-benzyl-2-hydroxy-3-[isobutyl-(2-inethylamino-bei-izothÎazole-6-sulfonyl)-amirio]-propyl} -2-(2)6-dimethyî-phenoxy)-acetamide; N-{3 -[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino] -1 -benzyl-2- hydroxypropyl}-3-fluoro-2-methyl-benzamide; N-{3-[(2-amino-benzotbiazo]e-6-su]fonyl)-isobutyl-amÎno]-l-benzyl-2- hydroxypropyl}-2-(4-aminomethyl-2,6-dtmethyl-phenoxy)-acetannde; {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid thiazol-5-ylmethyl ester; 3-amino-N-{l-benzyl-2-hydroxy-3-[isobntyl-(2-methylamino-benzothÎazole-6- sulfonyl)-amino}-propyl}-2-methyl-benzamide; {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid tetrahydro-furan-3-yl ester; N- {1 -benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfony(}-amino]-propyl}-3-hydroxy-2-methyl-benzamide; N- {3-[(2-ammo-benzothiazole-6-sulfonyl)-isobutyl-amino]-1 -benzyl-2- hydiOxypropyl}-2-(4-iodo-2,6-dimethy]-phenoxy)-acetamide; 012893 -15- 2-(4-amin.omethyl-236-diniethyl-phenoxy)-N-{l-benzyl-2-hydroxy-3-[isobutyl-(2- methylainino-benzothiazole-6-sulfonyl)-amino]-propyl}-acetamide; 2- (4-amino-2,6-dimethyl-phenoxy)-N-{l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-su]fonyl)-amino]-propyl}-acetamide;N-{l-beirzyl-2-hydroxy-3-[isobutyl-(2-rnethylamino-benzothiazole-6-sulfonyl)-amino]propyl}-4-bromo-2-methyl-benzamide; {1 -benzyl-2-hydroxy-3 -[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid oxazol-5-ylmethyl ester; 4-aoiïno-N- {1 -benzy l-2-hydroxy-3 - [isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-ammo]-propyl}-3-hydroxy-2-methyl-benzamide; their A-oxides and salts andthe stereoisomeric forms thereof.

Another group of interest includes {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester; {l-benzyl-3-[(2-dimethylamino-benzothiazole-6-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester;

N-{l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sidfonyÎ)-amÎnoJ propyl}-2-(2,6-dimethyl-phenoxy)-acetamide; N-{3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2- hydroxypropyl}-3-fluoro-2-methyl-benzamide; N- {3 -[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l -benzy 1-2- hydroxypropyl}-2-(4-aminomethyl-236-dimethyl-phenoxy)-acetamide; {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amïno]-propyl} -carbamic acid thiazol-5-ylmethyl ester; 3- amino-N-{l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-2-methyl-benzamide; {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-ainino]-propyl}-carbamic acid tetrahydro-fiiran-3-yl ester; N-{l-benzyl-2-hydroxy-3-[jsobutyl-(2-inethylamino-benzothiazole-6-sulfonyl)-amino} propyl}-3-hydroxy-2-methyl-benzamide; N-{3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2- hydroxypropyl}-2-(4-iodo-2,6-dimethyI-phenoxy)-acetamide; 2-(4-aminomethyl-2,6-diniethyl-phenoxy)-N-{l-benzyl-2-hydroxy-3-[isobuÎyl-(2- methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-acetamide; 2-(4-arnino-216-dilnethyl-phenoxy)-N-{l-benzyl-2-hydroxy-3-[isob^Ityl·(2- methylaniino-benzothiazole-6-sulfonyI)-amino]-propyI}-acetamide; 012893 -16- N-{l-benzyl-2-hydroxy-3-[isobutyl-(2-metliylamino-benzothiazole-6-sulfonyl)-amino]-propyl) -4-bromo-2-methyl-benzamide; {l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl} -carbamic acid oxazol-5-ylmethyl ester; 5 4-ammo-N-{l-benzyl-2-hydroxy-3-[Îsobutyl-(2-mefhylamino-benzothiazole-6- sulfonyl)-amino]-propyl}-3-hydroxy-2-methyl-benzamide; their Woxides and salts andthe stereoisomeric forms thereof.

Most preferred compounds are those enantiomeric forms of the compounds of formula 10 (I) or of the compounds belonging to any subgroup thereof having a ( 1 S,2JR.)-1 -benzyl- 2-hydroxy-propyl configuration.

Those compounds of formula (I) or those compounds belonging to any subgroup thereofin a hexahydro-furo[2,3-b]firran-3-yl ester foTm of the carbamic acid dérivative occur 15 preferably in a (3R,3aS,6aR) form such as, for instance, {(lS,2R)-3-[(2-amino- benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid

(3R,3aS,6aR)-hexahydro-fuiO[2,3-b]furan-3-yl ester

The compounds of formula (I) can generally be prepared using procedures analogous to20 those procedures described in WO 95/06030, WO 96/22287, WO 96/28418. WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205.

Particular reaction procedures to make the présent compounds are described below. Inthe préparations described below, the reaction products may be isolated from the medium 25 and, if necessary. further purïfied according to méthodologies generally known in the ailsuch as, for example, extraction, crystailization, trituration and chromatography.

Scheme A 012893 -17-

(a-6)

The 2-amino-6-chlorosulfonylbenzolhiazole dérivative (intermediate a-2) was prepaxedfollowing the procedure described in EP-A-0,445,926. Intermediates a-4 wereprepared by reacting an intermediate a-3, prepared according to the procedure 5 described in WO97/18205 and also depicted in scheme B, with an intermediate a-2 in areaction-inert solvent such as dichloromethane, and in the presence of a base such astriethylamine and at low température, for example at 0°C. The Boc group in theintermediate a-3 is aprotective feri-butyloxycarbonyl group. Another suitableprotective group such as phtalimido or benzyloxycarbonyl may conveniently replace it. 10 Intermediates a-4 may be deprotected with an acid such as hydrochloric acid in isopropanol or with trifLuoroacetic acid depending on the nature of the amino group inthe 2 position of benzoxazole, in a suitable solvent such as a mixture of éthanol anddioxane, thus preparing an intermediate a-5, Said intermediate a-5 may be furtherreacted with an intermediate of formula Rj-L-C(=O)-OH in the presence of a base such 15 as triethylamine (for alcohols to generate a carbamate) and optionally in the presence ofl-(3-dimethylaminopropyl)-3-ethyicarbodiimide hydrochloric acid (EDC) and 1-hydroxÿbenzotriazole (HOBT)(for carboxylic acids to generate an amide) or an alcoholsuch as ZerZ-butanol, and in a suitable solvent such as dichloromethane; thus formingintermediates a-6. 20 A convenient way of preparing compounds of formula (I) wherein both Rs and Re arehydrogen can be prepared analogously to the procedure described in scheme A, andwhereby one of Rj or Rg is replaced by a suitable protective group such as, forexample, an acetyl or an alkyloxycarbonyl group. In such a case, deprotection may 012893 -18- occur simultaneously with the deprotection of the nitrogen atom on the left-hand side ofthe molécule. A number of intermediates and starting materials used in the foregoing préparations areknown compounds, while others may be prepared according to art-knownméthodologies of preparing said or similar compounds.

Intennediate b-2, corresponding to intermediate a-3 in scheme A, may be prepared byadding an amine of formula H2N-R4 to an intennediate b-1 in a suitable solvent such asisopropanol.

In scheme B, enantiomerically pure compounds of formula b-2 are only obtained if b-1is enantiomerically pure. If b-1 is a mixture of stereoisomers, than b-2 will also consistof a mixture of stereoisomers.

The compounds of formula (I) may also be converted to the corresponding ZV-oxide.forms following art-known procedures for converting trivalent nitrogen into itsZV-oxideform. Said ZV-oxidation reaction may generally be carried out by reacting the startingmaterial of formula (I) with appropriate organic or inorganic pcroxide. Appropriateinorganic peroxides comprise, for example, hydrogen peroxide, alkali métal or earthalkaline métal peroxides, e.g. sodium peroxide, potassium peroxide; appropriateorganic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.3-chloro-benzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid,alkylhydroperoxides, e.g. fert-butyl hydroperoxide. Suitable solvents are, for example,water, lower alkanols, e.g. éthanol and the Iike, hydrocarbons, e.g. toluene, ketones,e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

The présent compounds can thus be used in animais, preferably in mammals, and inparticular in humans as phannaceuticals per se, in mixtures with one another or in theform of pharmaceutical préparations. 012893 -19-

Furthermore. the présent invention relates to pharmaceutical préparations that as activeconstïtuents contain an effective dose of at least one of the compounds of formula (I) inaddition to customary pharmaceutically innocuous excipients and auxiliaries. Thepharmaceutical préparations normally contain 0.1 to 90% by weight of a compound offormula (I). The pharmaceutical préparations can be prepared in a manner known perse to one of skill in the art. For this purpose, at least one of a compound of formula (I),together with one or more solid or liquid pharmaceutical excipients and/or auxiliariesand, if desired, in combination with other pharmaceutical active compounds. arebrought into a suitable administration form or dosage form which can then be used as apharmaceutical in human medicine or veterinary medicine.

Pharmaceuticals which contain a compound according to the invention can beadministered orally, parenterally, e.g., intravenously, rectally, by inhalation, ortopically, the preferred administration being dépendent on the individual case, e.g., theparticular course of the disorder to be treated. Oral administration is preferred.

The person skilled in the art is familiar on the basis of his expert knowledge with theauxiliaries that are suitable for the desired pharmaceutical formulation. Besidesolvents, gel-forming agents, suppository bases, tablet auxiliaries and other activecompound carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents,preservatives, solubilizers, agents for achieving a depot effect, buffer substances orcolorants are also useful.

Due to their favorable pharmacological properties, particularly thcir activity againstmulti-drug résistant HIV protease enzymes, the compounds of the présent invention areuseful in the treatment of individuals infected by HIV and for the prophyiaxis of theseindividuals. In general, the compounds of the présent invention may be useful in thetreatment of warm-blooded animais infected with viruses whose existence is mediatedby, or dépends upon, the protease enzyme. Conditions which may be prevented ortreated with the compounds ofthe présent invention, especially conditions associatedwith HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex(ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNSdiseases caused by retroviruses, such as, for example HIV mediated dementia andmultiple sclerosis.

Said method of treatment comprises the systemic administration to HTV-infectedsubjects of an amount effective to combat the conditions associated with HIV viruswith multi-drug résistant protease enzyme. 012893 -20-

The compounds of tihe présent invention may also find use in inhibiting ex vivo samplescontaining multi-drug résistant HIV-protease or expected to be exposed.to multi-drugrésistant HIV-protease. Hence, the présent compounds may be used to inhibit multi-drug résistant HIV-protease présent in a body fluid sample that contains or is suspectedto contain or be exposed to multi-drug résistant HTV-protease.

Also, the combination of an antirétroviral compound and a compound of the présentinvention can be used as amedicine. Thus, the présent invention also relates to aproduct containing (a) a compound of the présent invention, and (b) anotherantirétroviral compound, as a combined préparation for simultaneous, separatc orsequential use in treatment of retroviral infections, in particular, in the treatment ofinfections with multi-drug résistant HIV proteases, Thus, to combat or treat infectionswith multi-drug résistant HIV protease, or the infection and disease associated withsuch infections, such as Acquired Immunodeficiency Syndrome (AIDS) or AIDSRelated Complex (ARC), the compounds of this invention may be co-administered incombination with for instance, binding inhibitors, such as, for example, dextran sulfate,suramine, polyanions, soluble CD4, PRO-542, BMS-806; fusion inhibitors, such as, forexample, T20, T1249, 5-helix, D-peptide ADS-J1; co-receptor binding inhibitors, suchas, for example, AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK779; SHC-C (SCH351125), SHC-D, PRO-140RT inhibitors, such as, for example,foscarnet and prodrugs; nucleoside RTIs, such as, for example, AZT, 3TC, DDC, DDI,D4T, Abacavir, FTC, DAPD, dOTC, DPC 817; nucléotide RTIs, such as, for example,PMEA, PMPA (tenofovir); NNRTIs, such as, for example, nevirapine, delavirdine,efavirenz, 8 and 9-C1TIBO (tivirapine), loviride, TMC-125, dapivirine, MKC-442, UC781, UC 782, Capravirine, DPC 961, DPC963, DPC082, DPC083, calanolide A, SJ-1366, TSAO, 4"-deamÎnated TSAO, MV150, MV026048; RNAse H inhibitors, suchas, for example, SP1093V, PD126338; TAT inhibitors, such as, for example, RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L 708906, L 731988, S-1360; protease inhibitors, such as, for example, amprenavir and prodrug GW908,ritonavir, nelfinavir, saquinavir, indinavir, lopinavir, palinavir, BMS 186316,atazanavir, DPC 681, DPC 684, tipranavir, AG1776, mozenavir, GS3333, KNI-413,ΚΝΊ-272, L754394, L756425, LG-71350, PD161374, PD173606, PD177298,PD178390, PD178392, PNU 140135, TMC114 maslinic acid, U-140690: glycosylationinhibitors, such as, for example, castanospermine, deoxynojirimycine. Û 12893 -21-

The combination may in some cases provide a synergistic effect, whereby viralinfectivity and its associated symptoms may be prevented, substantially reduced, oreliminated completely. 5 The compounds of the présent invention may also be adnrinistered in combination withimmunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2,méthionine enkephalin, interferon alpha, HE-2000 and naltrexone) with antibiotics(e.g., pentamidine isothiorate) cytokines (e.g. Th2), modulators of cytokines,chemokines or the receptors thereof (e.g. CCR5) or hormones (e.g. growth hormone) to 10 ameliorate, combat, or eliminate HIV infection and its symptoms. Such combinationtherapy in different formulations may be administered simultaneously, separately orsequentially. Alternatively, such combination may be administered as a singleformulation, whereby the active ingrédients are released ffom the formulation simultaneously or separately. 15

The compounds of the présent invention may also be administered in combination withmodulators of the metabolization following application of the drug to an individual.These modulators include compounds that interfère with the metabolization atcytochromes, such as cytochrome P450. Some modulators inhibit cytochrome P450. It 20 is known that scvcral isoenzymes exist of cytochrome P450, one of which is cytochrome P450 3A4. Ritonavir is an example of a modulator of metabolization viacytochrome P450. Such combination therapy in different formulations may beadministered simultaneously, separately or sequentially. Alternatively, suchcombination may be administered as a single formulation, whereby the active 25 ingrédients are released tram the formulation simultaneously or separately.

Such modulator may be administered at the same or different ratio as the compound ofthe présent invention. Preferably, the weight ratio of such modulator vis-à-vis thecompound of the présent invention (modulatorcompound of the présent invention) is1:1 or lower, more préférable the ratio is 1:3 or lower, suitably the ratio is 1:10 or 30 lower, more suitably the ratio is 1:30 or lower.

For an oral administration form, compounds of the présent invention are mixed withsuitable additives, such as excipients, stabilizers or inert diluents, and brought by meansof the customary methods into the suitable administration forms, such as tablets, coated 35 tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inertcarriers are gum arabic, magnesia, magnésium carbonate, potassium phosphate, lactose,glucose, or starch, in particular, cornstarch. In this case the préparation can be carriedout both as dry and as moist granules, Suitable oily excipients or solvents are vegetable 012893 -22- or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous oralcoholic solutions are water, éthanol, sugar solutions, or mixtures thereof.

Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries forother administration forms.

For subcutaneous or intravenous administration, the active compounds, if desired withthe substances customaiy therefore such as solubilizers, emulsifiers or furtherauxiliaries, are brought into solution, suspension, or émulsion. The compounds offormula (I) can also be lyophilized and the lyophilizates obtained used, for example, forthe production of injection or infusion préparations. Suitable solvents are, for example,water, physiological saline solution or alcohols, e.g. éthanol, propanol, glycerol, inaddition also sugar solutions such as glucose or mannitol solutions, or altemativelymixtures of the various solvents mentioned.

Suitable phannaceutical formulations for administration in the form of aérosols orsprays are, for example, solutions, suspensions or émulsions ofthe compounds offormula (I) or their physiologically tolerable salts in a pharmaceutically acceptablesolvent, such as éthanol or water, or a mixture of such solvents. If required, theformulation can also additionally contain other pharmaceutical auxiliaries such assurfactants, emulsifiers and stabilizers as well as a propellant. Such a préparationcustomarily contains the active compound in a concentration ffom approximately 0.1 to50%, in particular ffom approximately 0.3 to 3% by weight.

In order to enhance the solubility and/or the stability ofthe compounds of formula (I) inpharmaceutical compositions, it can be advantageous to etnploy a-, β- or γ-cyclo-dextrins or their dérivatives. Also co-solvents such as alcohols may improve thesolubility and/or the stability ofthe compounds of formula (I) in pharmaceuticalcompositions. In the préparation of aqueous compositions, addition salts ofthe subjectcompounds are obviously more suitable due to their increased water solubility.

Appropriate cyclodextrins are α-, β- or γ-cyclodextrins (CDs) or ethers and mixedethers thereof wherein one or more of the hydroxy groups of tbe anhydroglucose unitsof the cyclodextrin are substituted with Ci-ealkyl, particularly methyl, ethyl orisopropyl, e.g. randomly methylated β-CD; hydroxy Ci.«alkyl, particularly hydroxy-ethyl, hydroxypropyl or hydroxybutyl; carboxyCi-6alkyl, particularly carboxymethyl orcarboxyethyl; Ci-6alkyl-carbonyl, particularly acetyl; Ci_6alkyloxycarbonylCi^aIkyl orcarboxyCi-6alkyloxyCi-salkyl, particularly carboxymethoxypropyl or carboxyethoxy-propyl; Ci-ealkylcarbonyloxyCi-salkyl, particularly 2-acetyloxypropyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 012893 -23- 2,6-dimethyl-p-CD, 2-hydroxyethyl-3-CD, 2-hydroxyethyl-y-CD, 2-hydroxy-propyl-y-CD and (2-carboxymethoxy)propyl-P-C.D, and in particular 2-hydroxy-propyl-p-CD (2-HP-P-CD).

The term mixed ether dénotés cyclodextrin dérivatives wherein at least twocyclodextrin hydroxy groups are etherified with different groups such as, for example,hydroxy-propyl and hydroxyethyl.

An interesting way of formulating the présent compounds in combination with acyclodextrin or a dérivative thereof has been described in EP-A-721,331. Although theformulations described therein are with antifungal active ingrédients, they are equallyinteresting for formulating the compounds of the présent invention. The formulationsdescribed therein are particularly suitable for oral administration and comprise anantifungal as active ingrédient, a sufficient amount of a cyclodextrin or a dérivativethereof as a solubilizer, an aqueous acidic medium as bulk Iiquid carrier and analcohoiic co-solvent that greatly simplifies the préparation of the composition. Saidformulations may also be rendered more palatable by adding phannaceuticallyacceptable sweeteners and/or flavors.

Other convenient ways to enhance the solubility of the compounds of the présentinvention in pharmaceutical compositions are described in WO 94/05263, WO 98/42318, EP-A-499,299 and WO 97/44014, ali incorporated herein by reference.

More in particular, the présent compounds may be formulated in a pharmaceuticalcomposition comprising a therapeutically effective amount of particles consisting of asolid dispersion comprising (a) a compound of formula (I), and (b) one or morepharmaceutically acceptable water-soluble polymers.

The term "a solid dispersion" defines a System in a solid State (as opposed to a Iiquid orgaseous State) comprising at least two components, wherein one component isdispersed more or less evenly throughout the other component or components. Whensaid dispersion of the components is such that the System is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined in thermo-dynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions arepreferred physical Systems because the components therein are usually readilybioavailable to the organisais to which they are administered.

The term "a solid dispersion" also comprises dispersions that are less homogenousthroughout than solid solutions. Such dispersions are not chemically and physically 012893 -24- uniform throughout or comprise more than one phase.

The water-soluble polymer in the particles is conveniently a polymer that has anapparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution ai 20°Csolution.

Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC.HPMC having a methoxy degree of substitution fiom about 0.8 to about 2.5 and ahydroxypropyl molar substitution from about 0.05 to about 3.0 is generally watersoluble. Methoxy degree of substitution refers to the average number of methyl ethergroups présent per anhydroglucose unit of the cellulose molécule. Hydroxy-propylmolar substitution refers to the average number of moles of propylene oxide that hâvereacted with each anhydroglucose unit of the cellulose molécule.

First preparing a solid dispersion of the components, and then optionally grinding ormilling that dispersion allows one to préparé the particles as defined hereinabove.Various techniques exist for preparing solid dispersions including melt-extrusion,spray-drying and solution-évaporation, melt-extrusion being preferred.

It may further be convenient to formulate the présent compounds in the form ofnanoparticles which hâve a surface modifier adsorbed on the surface thereof in anamount sufficient to maintain an effective average particle size of less than 1000 nm.Useful surface modifiera are believed to include those that physically adhéré to thesurface of the antirétroviral agent but do not chemically bond to the antirétroviral agent.

Suitable surface modifiera can preferably be selected from known organic andinorganic pharmaceutical excipients. Such excipients include various polymers, lowmolecular weïght oligomers, naturai products and surfactants. Preferred surfacemodifiera include nonionic and anionic surfactants.

Yet another interesting way of formulating the présent compounds involves a pharma-ceutical composition whereby the présent compounds are incorporated in hydrophilicpolymers and applying this mixture as a coat film over many small beads, thus yieldinga composition with good bioavailability which can conveniently be manufactured andwhich is suitable for preparing pharmaceutical dosage forms for oral administration.

Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of ahydrophilic polymer and an antirétroviral agent and (c) a seal-coating polymer layer. 012893 -25-

Materials suitable for use as cores in the beads are manifold, provïded that saidmateriels aie pharmaceutically acceptable and liave appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances, organicsubstances, and saccharides and dérivatives thereof.

The route of administration may dépend on the condition of the subject, co-medicationand the like.

Another aspect of the présent invention concems a ldt or container comprising acompound of formula (I) in an amount effective for use as a standard or reagent in atest or assay for determining the ability of a potential pharmaceutical to inhibit multi-drug résistant HIV protease, HIV growth, or both. This aspect of the invention mayfind its use in pharmaceutical research programs.

The compounds of the présent invention can be used in phenotypic résistancemonitoring assays, such as known recombinant assays, in the clinical management ofrésistance developing diseases such as HIV. A particularly useful résistancemonitoring System is a recombinant assay known as the Antivirogram™. TheAntivirogram™ is a highly automated, high throughput, second génération,recombinant assay that can measure susceptibility, especially viral susceptibility, to thecompounds of the présent invention. (Hertogs K, de Bethune MP, Miller V et al.Antimicrob Agents Chemother, 1998; 42(2):269-276, incorporated by reference).

Interestingly, the compounds of the présent invention may comprise chemicallyreactive moieties capable of forming covalent bonds to localized sites such that saidcompound hâve increased tissue rétention and half-lives. The term “chemically reactivegroup” as used herein refers to chemical groups capable of forming a covalent bond.Reactive groups will generally be stable in an aqueous environment and will usually becarboxy, phosphoryl, or convenient acyl group, either as an ester or a mixed anhydride,or an imidate, or a maleimidate thereby capable of forming a covalent bond withfunctionalities such as an amino group, a hydroxy or a thiol at the target site on forexample blood components such as albumine. The compounds ofthe présent inventionmay be linked to maleimide or dérivatives thereof to form conjugates.

The dose of the présent compounds or of the physiologically tolerable salt(s) thereof tobe administered dépends on the individual case and, as customary, is to be adapted tothe conditions ofthe individual case for an optimum effect. Thus it dépends, of course,on the frequency of administration and on the potency and duration of action of thecompounds employed in each case for therapy or prophylaxis, but also on the nature 012893 -26- and severity of the infection and symptoms, and on the sex, âge, weight, co-medication,and individual responsiven.es s of the human or animal to be treated and on whether thetherapy ïs acute or prophylactic. Customarily, the daily dose of a compound of formula(I) in the case of administration to a patient approximaîely 75 kg in weight is 1 mg to3g, suitably 1 mg to lg, preferably 3 mg to 0.5 g, more preferably 5 mg to 300 mg. Thedose can be administered in the form of an individual dose, or divided into several, e.g.two, three, or four, individual doses.

Experimental Part

Préparation of the compounds of formula (I)

The nomenclature used throughout the description is based on Chemical AbstractsServices Nomenclature.

Example 1 : Compound 2

To a mixture of 825 mg 2-amino-benzothiazole-ô-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl amide and 373 mg triethylamine in dichloromethane was added452 mg l-[[[[(3R,3aS,6aR)-hexahydrofuro[2:3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidine-dione (described in W09967417). This mixture was stirred at roomtempérature for 12 hours. After évaporation of dichloromethane under reduced pressure,the crude product was purifîed on silica, yielding 270 mg 24.8 % compound 2.·

Example 2 : Compound 4

To a mixture of 350 mg 2-methylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl amide and 200 mg triethylamine in dichloromethanewas added 210 mg 1 -[[[[hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione (described in W09967417). This mixture was stirred at roomtempérature for 12 hours. After évaporation of dichloromethane under reduced pressure,the crude product was purifîed on silica, yielding 260 mg (55 %) of compound 4.

Example 3 : Compound 6

To a mixture of 420 mg 2-dimethylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyI)-isobutyl amide and 98 mg triethylamine in dichloromethanewas added 230 mg l-[[[[hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidïnedione (described in W09967417). This mixture was stirred at roomtempérature for 12 hours. After évaporation of dichloromethane under reduced pressure,the crude product was purifîed on silica, yielding 500 mg 90 % of compound 6.

Example 4 : Compound 17 012893 -27- A mixture of 800 mg of 2-amino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl amide, 50 mg of HOBT (hydroxybenzotriazol), 420 mg of EDCand 668 mg of (3,4,5-trimethyl-benzyl)-carbamic acid tert-butyl ester compound withhydroxy acetic acid in 80 ml of dichloromethane, was stirred overnight at roomtempérature. The réaction mixture was then washed with water and brine. The organiclayer was separated, dried and the solvent evaporated. The residue was purified bycolumn chroxnatography, yielding 1 g (75 %) of [4-({3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropylcarbamoyl}-methoxy)-3,5-diniethyl-benzylj-carbamic acid tert-butyl ester. This intermediate (500 mg) was further dissolvedin methanol (20 ml) and 10 ml of a solution of HCl in isopropanol (5 to 6 N) was addeddropwise. The mixture was stirred overnight at room température. The solvent wasevaporated and the residue was purified on silica yielding 190 mg of compound 17(43%).

Example 5 : Compound 27 A mixture of 134 mg of 2-methylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl amide, 4 mg of HOBT (hydroxybenzotriazol), 66 mgof EDC and 63 mg of 4-bromo-2-methyl benzoic acid in dichloromethane, was stirredovernight at room température. The reaction mixture was then washed with water andbrine. The organic layer was separated, dried and the solvent evaporated. The residuewas purified by préparative HPLC yielding 25 mg (13 %) of compound 27.

Example 6 : Compound 28

To a mixture of 4.48 g 2-methylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl)-isobutyl amide and 2.73 g triethylamine in dichloromethanewas added 3.45 g carbonic acid 2,5-dioxo-pyrrolidin-l-yl ester oxazol-5-ylmethyl ester.This mixture was stirred at room température for 12 hours. After évaporation ofdichloromethane under reduced pressure, the crude product was purified on silica,yielding 1.02 g 19 % compound 28.

The compounds in Table 1, not intended to be limiting the scope of the présentinvention, hâve been prepared analogous to one ofthe above examples and tested insupport of the presently claimed invention ;

Table 1

Name Number {(lS,2R)-3-[(2-amÎno-benzotbiazole-6-sulfonyl)-isobutyl-amÎno]-l-benzyl-2-hydroxypropyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 1 {(lS,2R)-3-[(2-amino-benzothiazole-6-sulfony])-isobutyl-amino]-l-benzyl-2- 2 012893 -28- hydroxypropyl}-carbamic acid (3R,3aS,6aR)-hexahydro-iuro[2,3-b]furan-3-yl ester {(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid thiazol-5-ylmethyl ester 3 {(1S ,2R)-1 -benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 4 {(1S ,2R)-1 -benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl} -carbamic acid (3R,3 aS,6aR)-(hexahydro-furo[2,3-b]furan-3-yl) ester 5 {( 1S ,2R)-1 -benzy l-3-[(2-dimethv lamino-benzothiazole-6-sulfonyl)-isobu.tyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-&r.o[2,3-b]furan-3-yl ester 6 {(lS,2R)-3-[(2-amino-benzotiiiazole-6-sulfonyl)-isobutyl-aniino]-l-benzyl-2-hydroxypropyl}-carbamic acid benzyl ester 7 N- {( 1 S,2R)-3 -[(2-amino-benzothiazole-6-sulfony l)-isobutyl-amino]-1 -benzyl-2-hydroxypropyl}-2-(2,6-dimethy]-phenoxy)-acetaaiide 8 {(lS,2R)-3-[(2-amino-benzot!ii.azole-6-sulfonyl)-isobutyl-amino}-l-benzyl-2-hydroxypropyl}-carbamic acid pyridin-3-ylmethyl ester 9 3-amino-N- {(1 S,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-am ino]-1 -benzyl-2-liydroxypropyl}-2-methyl-benzamide 10 N-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-3 -hydroxy-2-methyl-benzamide 11 {(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2-hydroxypropyl}-carbamic acid tetrahydro-furan-3-yl ester 12 {( 1S ,2R)-3 -[(2-ainino-benzothiazole-6-sulfonyl)-isobÎityl-ammo]-1 -benzyl-2-bydroxypropyl}-carbamic acid (S) (tetxahydro-furan-3-yl) ester 13 N- {(1 S,2R)-3 -[(2-amino-benzothiazole-6-s ulfonyl)-isobutyl-araino]-l -benzy 1-2-hydroxypropyl} -2-methyl-benzamide 14 N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6- sulfonyl)-amino]-propyl}-2-(2,6-dimethyl-phenoxy)-acetamide; 15 N-{(lS>2R)-3-[(2-amiIlo-benzothiazole-6-sulfonyl)-isobutyl·amirLo]-ί-benzyi-2- hydroxypropyl}-3-fluoro-2-methyl-benzamide 16 N-{(lS,2R)-3-[(2-amino-benzothiazole-6-sulfonyl)-isobutyl-amino]-l-benzyl-2- hydroxypropyl}-2-(4-aminomethyl-2,6-dimethyl-phenoxy)-acetamide 17 {(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl} -carbamic acid thiazol-5-ylmethyl ester 18 {(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid thiazol-5-ylmethyI ester trifluoroacetate 19 3-amino-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylammo- 20 12893 -29- benzothiazole-6-sulfonyl)-amino]-propyl}-2-methyl-benzamide trifiuoroacetate {(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylanûno-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid (S) (tetrahydro-furan-3-yl) ester 21 {(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid (S) (tetrahydro-ftiran-3-yl) ester trifiuoroacetate 22 N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-3-hydroxy-2-methyl-benzamide trifiuoroacetate 23 N-{(lS,2R)-3-[(2-ammo-benzothiazole-6-sulfonyr)-isobutyl-amino]-l-benzyl-2- hydroxypropyl}-2-(4-iodo-2,6-diinethyl-phenoxy)-acetamide 24 2-(4-aminomethyl-2,6-dimethyl-phenoxy)-N- {(1 S,2R)-1 -benzyl-2-hydroxy-3 -[isobutyl-(2-methylamino-benzothiazole-6-sulfonyl)-amino]-propyl}-acetamide 25 2-(4-amino-2J6-dimethyl-phenôxy)-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[Isobutyl-(2- methylamino-benzothiazo]e-6-suIfonyl)-amino]-propyl}-acetamide 26 N-{(lSi2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-metlrylarnino-benzothÎazole-6- sulfonyl)-amino]-piOpyl}-4-bromo-2-methyl-benzamide 27 {( 1 S,2R)-1 -benzyl -2-h.y droxy-3-[isobutyl-(2-inethylammo-benzothiazole-6-sulfonyl)-amino]-propyl}-carbamic acid oxazol-5-ylmethyl ester 28 4-amino-N-{(lS,2R)-l-benzyl-2-hydroxy-3-[isobutyl-(2-niethylamino- benzothiazole-6-suIfonyl)-ammo]-propyl}-3-hydroxy-2-methyl-benzamide 29

Antiviral analyses:

The compounds of the présent invention were examined for anti-viral actïvity in acellular assay. The assay demonstrated that these compounds exhibited potent anti- 5 HIV activity against a wild type laboratory HIV strain (HIV-1 strain LAI). The cellularassay was performed according to the following procedure.

Cellular Assay Experimental Method: HIV- or mock-infected MT4 cells were incubated for five days in lhepresence of 10 various concentrations of the inhibitor. At the end of the incubation period, the replicating virus in the control cultures has killed ail HIV-infected cells in the absenceof any inhibitor. Cell viability is measured by measuring the concentration of MTT, ayellow, water soluble tétrazolium dye that is converted to a purple, water insolubleformazan in the mitochondria of living cells only. Upon solubilization of the resulting 15 formazan crystals with isopropanol, the absorbance of the solution is monitored at540nm, The values correlate directly to the number of living cells remaining in theculture atthe completion of the five-day incubation. The inhibitory activity of thecompound was monitored on the virus-infected cells and was expressed as EC50 and 012893 -30- EC90. These values represent the amount of the compound required to protect 50% and90%, respectively, of the cells fiom the cytopathogenic effect of the virus. The toxicityof the compound was measured on the mock-infected cells and was expressed as CC50,which represents the concentration of compound required to inhibit the growth of the.cells by 50%. The selectivity index (SI) (ratio CC50/EC50) is an indication of theselectivity ofthe anti-HIV activity of the inhibitor. Wherever results are reported as e.g.pECso or pCCso values, the resuit is expressed as the négative logarithm of the resuitexpressed as EC50 or CC50 respectively.

Antiviral spectrum:

Because of the increasing emergence of drug résistant HIV strains, the présentconrpounds were tested for their potency against clinically isolated HIV strainsharboring several mutations (Table 2 and 3). These mutations are associated withrésistance to protease inhibitors and resuit in viruses that show various degrees ofphenotypic cross-resislance to the currently commercially available drugs such as forinstance saquinavir, ritonavir, nelfïnavir. indinavir and amprenavir.

Table 2 List with a représentative sélection of mutant HIV strains (A to F).

Strnin Mutations in HIV protease gene A V003I, L0I0I, V032T, L033M, E035D, S037Y, S037D, M046I, R057R/K, Q058E, L063P, K070T, A071V, I072V, I084V, L089V B V003I, LO101, K.020R, E035D, M036I, S037N, Q058E, I062V, L063P, À071V, I072M, G073S, V0771,1084V, I085V, L090M C V003I, L0101,1015V, L019I, K020M, S037N, R041K, I054V, Q058E, L063P, A071V, I084V, L090M, I093L D V0031, L010L/I. I013V, L033I, E035D, M036I, M046L, K055R, R057K, L063P, I066F, A071V, I084V, NO88D, L090M E V003I, L010I, V0111, A022V, L024I, EO35D, M036I, S037T, R041K, I054V, 1062V, L063P, À071V, I084V F L010F, M046I, M071V, I084V

Results:

As a measure of the broad spectrum activity of the présent compounds, Table 3 showsthe results of the antiviral testing in terins of pECso.(= -log of ECso). The foldrésistance (FR), defined as FR = EC50 (mutant stram)/EC5o(HIV-l strain LAI) is listedin Table 4. For rnost of the compounds the fold résistance ranges between 0.1 and 1OO.Thus, the présent compounds are potent inhibitors of a broad range of mutant strains. 01289 -31’

The toxicity (Tox) is expressed as the pCCso value as determined with mock transfectedcells while the pECso for the wild type is displayed in column WT.

Table 3. Results of the toxicity testing and the résistance testing against strain A to F5 (expressed as pEC5o).

Compound Strain A Strain B Strain C Strain D Strain E Strain F Tox WT 1 8,53 8.44 8.38 8.65 8.51 ND 4.16 8.26 2 8.68 8.59 8.54 8.69 8.50 8.45 4.07 8.18 3 7,52 8.05 7.81 7.44 7.66 7.27 4.13 8.34 4 8.44 8.93 8.93 8.93 8.89 8.06 <5 9.34 5 9.37 9.57 9.71 ND ND 8.71 4.15 9.26 6 6.70 6.89 7.47 6.96 ND 6.15 <4 8.4 7 6.37 7.53 7.49 6.93 7.36 6.11 4.33 8.23 8 7.5 7.87 7.59 7.47 7.56 6.85 <5 8.18 9 6.58 8.25 5.31 7.38 7.62 ND 4.29 8.31 10 7.07 8.03 7.80 7.64 7.88 7.06 4.14 8.04 11 6.95 8.14 8.12 8.08 8.14 6.99 4.24 7.84 12 6.64 8.12 6.72 7.58 8.11 ND <4 8.37 13 7.39 8.24 8.42 8.13 8.57 6.98 <4 8.52 14 6.05 7.57 6.75 7.40 7.52 ND 4,33 8.42 15 7.29 7.54 7.40 7.30 7.44 6.64 4.04 7.95 16 <4 <4 <4 <4 <4 <4 4.95 5.85 17 7.50 ' 8.18 7.91 7.63 8.12 6.80 4.2 8.15 18 7.51 8.21 8.13 7.67 8.04 6.83 4.07 8.72 19 7.36 7.80 7.88 7.43 7.90 6.80 ND 8.51 20 6.50 7.61 7.40 7.38 7.59 6.12 <4 8.32 22 6.93 7.83 8.19 7.78 8.36 6.1 <4 8.84 23 6.54 8.02 8.06 7.67 8.14 5.20 4.16 8.34 25 7.36 7.70 7.75 7.39 7.76 6.32 4.85 8.39 26 7.52 8.40 8.14 8.08 8.21 7.25 ND 8.57 27 6.80 7.69 5.30 7.07 7.51 6.19 <4 7.72 28 7.71 8.25 8.21 7.43 8.15 7.11 ND 8.60 ND means not determined

Some compounds hâve been tested for an even broader range of mutant HIV protease10 viruses. For instance, compound 1 was tested against a panel of more than 20 mutant 012893 -32- proteases whereby compound 1 had apICso value of 9,13 for the most sensitive mutantand a pICso value of 8.12 for the most résistant mutant. This indicates tliat ail themutants within this set of more that 20 mutant proteases are sensitive within a narrowwindow of IC50 values and thus also in fold résistance values.

Table 4 : fold résistance

Compound Strain A Strain B Strain C Strain D Strain E Strain F 1 0.5 0.7 0.8 0.4 0.6 2 0.3 0.4 0.4 0.3 0.5 0.5 3 6.6 1.9 3.4 7.9 4.8 11.7 4 7.9 2.6 2.6 2.6 2.8 19.1 5 0.8 0.5 0.4 3.5 6 50.1 32.4 8.5 27.5 177.8 7 72.4 5.0 5.5 20.0 7.4 131.8 8 4.8 2.0 3.9 5.1 4.2 21.4 9 53.7 1.1 1000.0 8.5 4.9 « 10 9.3 1.0 1.7 2.5 1.4 9.5 11 7.8 0.5 0.5 0.6 0.5 7.1 12 53.7 1.8 44.7 6.2 1.8 - 13 13.5 1,9 1.3 2.5 0.9 34.7 14 234.4 7.1 46.8 10.5 7.9 15 4.6 2.6 3.5 4.5 3.2 20.4 17 4.5 0.9 1.7 3.3 1.1 22.4 18 16.2 3.2 3.9 11.2 4.8 77.6 19 14.1 5.1 4.3 12.0 4.1 51.3 20 66.1 5.1 8.3 8.7 5.4 158.5 22 81.3 10.2 4.5 11.5 3.0 549.5 23 63.1 2.1 1.9 4.7 1.6 1380.4 25 10.7 4.9 4.4 10.0 4.3 117.5 26 11.2 1.5 .2.7 3.1 2.3 20.9 27 8.3 1.1 263.0 4.5 1.6 33.9 28 7.8 2.2 2.5 14.8 2.8 30.9

Protein Binding analyses:

Human sérum proteins like albumin (HSA) or alpha-1 acid glycoprotein (AAG) are10 known to bind many drugs, resulting in a possible decrease in the effectiveness of the 012893 -33- drug. In order to détermine whether the présent compounds would be adverselyeffected by this binding, the anti-HIV activity of some of the présent compounds wasmeasured in the presence of human sérum, thus evaluating the effect of the binding ofthe protease inhibitors to those proteins. MT4 cells are infected with HIV-1 LAI at a multiplicity of infection (MOI) of 0.001 -0.01 CCID50 (50% cell culture infective dose per cell, CCID50)· After 1 h incubation,cells are washed and plated into a 96 well plate containing serial dilutions of thecompound in the presence of 10% FCS (foetal calf sérum), 10% FCS + 1 mg/ml AAG(ai-acid glycoprotein), 10% FCS + 45 mg/ml HSA (human sérum albumin) or 50%human sérum (HS). After 5 or 6 days incubation, the EC50 (50% effective concentrationin cell-based assays) is calculated by determining the cell viability or by quantifying thelevel of HIV réplication. Cell viability is measured using the assay described above. Intoa 96 well plate containing serial dilutions of the compound in the presence of 10% FCSor 10% FCS + 1 mg/ml AAG, HIV (wild type or résistant strain) and MT4 cells areadded to a final concentration of 200-250 CCIDso/well and 30,000 cells/well,respectively. After 5 days of incubation (37°C, 5% CO2), the viability of the cells isdetermined by the tétrazolium colorimétrie MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-di-phenyltetrazolium bromide) method (Pauwels et al. J Virol. Methods 1988, 20, 309321).

Pharmacokinetic data

The pharmacokinetic properties of some compounds of formula (I) were tested on ratsand dogs. The compounds were evaluated in Whistar rats, source Iffa Credo, weighingapproximately 350 g. Before dosing the animais were fasted overnight (approximately12 h fasting period). The compounds wcrc dissolvcd in DMSO or PEG 400. Theresults represented in the table concem the results from the oral or intra-peritonealdosing of the compounds. Blood was sampled at 30 min, lh, 2h, 3h, no pre-dosesample was taken. The amount of the compound in the biological sample wasdetennined using LC-MS. In the table below “or” means oral dosing, “ip” rneans intra-peritoneal dosing, “mpk” means mg per kilogram. The results are illustrated in Table 5.

Table 5

Compound Cmax (ng/ml) conditions (results normalized to lOmpk) 2 427 after 30 minutes ip, rat, DMSO 2 52 after 30 minutes or, rat, PEG400 4 1668 after 30 minutes ip, rat, DMSO 4 348 after 30 minutes or, rat, DMSO 4 225 after 30 minutes or, rat, PEG400 15 86 after 30 minutes ip, rat, DMSO 15 10 after 1S0 minutes or, rat, PEG400

-34- 18 1141 after 240 minutes ip, rat, DMSO 18 396 after 30 minutes or, rat, DMSO 18 668 after 15 minutes or, rat, PEG400 18 15 after 60 minutes or, dog, DMSO 18 42 after 30 minutes or, dog, PEG400 21 1763 after 15 minutes ip, rat, DMSO 21 1139 after 15 minutes or, rat, DMSO 21 1315 after 15 minutes or, rat, PEG400 21 61 after 120 minutes or, dog, PEG400 - 2 animais 21 184 after 30 minutes or, dog, PEG400 - 4 animais 25 453 after 30 minutes ip, rat, DMSO 28 1003 after 30 minutes ip, rat, DMSO 28 540 after 30 minutes or, rat, DMSO 28 430 after 60 minutes or, rat, PEG400

For mutation

Active ingrédient, in casu a compound of formula (I), is dissolved in organic solventsuch as éthanol, methanol or methylene chloride, preferably, a mixture of éthanol and 5 methylene chloride. Polymers such as polyvinylpyrrolidone copolymer with vinylacetate (PVP-VA) or hydroxypropylmethylcellulose (HPMC), typically 5 mPa.s. aredissolved in organic solvents such as éthanol, methanol methylene chloride. Suitablythe polymer is dissolved in éthanol. The polymer and compound solutions are mixedand subsequently spray dried. The ratio of compound/polymer can be selected from 1/1 10 to 1/6. Intermediate ranges were 1/1.5 and 1/3. The spraydried powder, a solid dispersion, is subsequently filled in capsules for administration. The drug load in onecapsule dépends on the capule size used.

Film-coated Tablets 15 Préparation of Tablet Core A mixture of 100 g of active ingrédient, in casu a compound of formula (I), 570 glactose and 200 g starch was mixed well and thereafter humidified with a solution of5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml ofwater.

The wet powder mixture was sieved, dried and sieved again. Then there was added 100 20 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The wholc was mixedwell and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of theactive ingrédient.

Coating

To a solution of 10 g methylcellulose in 75 ml of denaturated éthanol there was added a 25 solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then there were added75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycolwas molten and dissolved in 75 ml of dichloromethane. The latter solution was added 012893 -35- to the former and then there were added 2,5 g of magnésium octadecauoate, 5 g ofpolyvinylpyrrolidone and 30 ml of concentrated color suspension and the whole washomogenated. The tahlet cores were coated with the thus obtained mixture in a coatingapparatus. 5

Claims (19)

36 CLAIMS 1. The use of a 2-amino-benzothiazole, having the formula a Λ-oxide, known, stereoisomeric form, racexnic mixture, prodrug, ester or metabolite5 thereof, thereof Ri is hexahydroforo [2,3-b] ftiranyl, tetrahydrofaranyl, oxazolyl, thiazolyl, pyridinyl, orphenyl optionally substituted with one or more substituents independentlyselected from C 1-4 alkyl, hydroxy, amino, halogen, aminoC 1-6 alkyl and mono (C 1-4 alkyl) amino; R21S hydrogen or Cylyl; L is a direct bond, -O-, C1-6alkanediyl-O- or -O-C1-6alkanediyl; R3 is phenylCyclyl; R4 is C1-C6alkyl; R5 is hydrogen or C₁ alkyl alkyl; R 6 is hydrogen or C 1-6 alkyl; in the manufacture of a drug useful for inhibiting mutant HIV protease in arnammal infected with mutant mutant HIV protease. 2. The use of claim is one of the following: R3 is phenylmethyl; R4 is C] -4alkyl, preferably isobutyl; Rs is hydrogen or methyl; R4 is hydrogen or methyl, 25 3. R5 is methyl or hydrogen and Rs is hydrogen R5 and R6 are hydrogen.30 · 5. L-R 1 is -O- (hexahydrofuro [2,3-b] furanyl), -O-tetrahydrofuranyl, -O-methyl- (optionally substitutedphenyl), - O-methyl-pyridinyl, -O-methyl-thiazolyl, -O-methyl-thiazolyl, -methyl-O- (optionally substituted phenyl) or optionally substituted phenyl. 35 012893 37 6. compound (3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -carbamic acid hexahydro- furo [2,3-b] fiiran-3-yl ester; {3 - [(2-amino-benzothiazole-6-sulfonyl) isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid thiazol-5-ylmethyl ester; {1-Benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -propyl} -carbamic acid h.exahydro-furo [2,3-b] furan-3- {1-Benzyl · 3 - [(2-dimethylamino-benzothiazol-6-sulfonyl) -isobutyl-amino] -2-hydroxy-propyl} -carbamic acid hexahydro-furo [2,3-b] furan-3-yl ester -yl ester; {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} carbamic acid benzyl ester; N- {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2- (2,6-dimethylphenoxy) acetamide; {3 - [(2-amino-benzothiazol-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -carbamic acid pyridin-3-ylmethyl ester; 3-amino-N- {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2-methylbenzamide; N- {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl) -3-hydroxy-2-methylbenzamide; {3 - [(2-amino-benzothiazol-6-sulfonyl) -isobutylamino] -1-benzyl-2-hydroxypropyl} -carbamic acid tetrahydro-furan-3-yl ester; N- {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutyl-anilino] -1-benzyl-2-hydroxypropyl} -2-methyl-benzamide; N- {l-benzyl-2-hydroxy-3- [isobxityl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -2- (2,6-dimethyl-phenoxy) -acetamide; -N- {3 - [(2-amino-benzothiazole-6-su] sulfonyl) -isobutyl-amino] -l-benzyl-2-hydroxypropyl} -3-fluoro-2-methyl-benzamide; N- {3- [(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -l-benzyl-2-hydroxypropyl} -2- (4-aminomethyl-2,6-dimethyl-phenoxy) -acetamide; {l-benzyl- 2-hydroxy-3- [isobutyl- (2-ethylamino-benzothiazol-6-sulfonyl) -amino] -propyl} -carbamic acid thiazol-5-ylmethyl ester; 3-Amino-N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylaminomethylbenzothiazole-6-yl) yl] amino} propyl} -2-methylbenzamide; {1-Benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -propyl} -carbamic acid tetrahydro-furan-3-yl ester; N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylammo-benzothiazol-6-sulfonyl) -amino] -propyl} -3-hydroxy-2-methyl-benzamide; N- {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2- (4-iodo-2,6-dimethylphenoxy) - acetamide; 2- (4-Aminomethyl-2,6-dimethyl-phenoxy) -N- {1-benzyl-2-hydroxy-3 - [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} - acetamide; 2- (4-Amino-2,6-dimethyl-phenoxy) -N- (1-benzyl-2-hydroxy-3- [isobutyl- (2-methylammobenzothiazole-6-sulfonyl) -amino] -propyl} - acetamide; N- (1-Benzyl-2-hydroxy-3-isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -propyl} -4-bromo-2-methyl-benzamide; 1-benzyl-2 hydroxy-3- [isobutyl- (2-methylaminobenzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid oxazol-5-ylmethyl ester, 4-amino-N- {1-benzyl-2-hydroxy-4-amino-N- 3- [Isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -3-hydroxy-2-methyl-benzamide, which is known to be a stereoisomeric form tbereof. 7. The mutated HTV protease mutant base at least one mutation at a position selected from 10, 71 and 84. 8. Resistance of the protease for the compound described in any claim 1 to 6 rangesbetween 0.01 and 100. 9. A compound having the formula a 7V-oxide, known, stereoisomeric form, racemic mixture, prodrug, ester or metabolitethereherehereof, Ri is hexahydrofuro [2.3-b] furanyl, tefrah.ydrofuran.yl, oxazolyl, thiazolyl, pyridinyl, orphenyl optionally substituted with one or more substituents independentlyselected from Cnsalkyl, hydroxy, amino, halogen, aminoC1alkyl and (C 1-4 alkyl) amino; Kings hydrogenorCi_6alky]; L is a direct bond, -O-, C 1-6 alkanediyl-O-or -O-C 1-6 -alkanediyl; R 3 is phenylC 1-4 alkyl; R4 is C1-Fialkyl; Rs is hydrogen or C1-alkyl; R is hydrogen or C 1-6 alkyl; 012893 39 provided that the compound is other than: {(1S, 2R) -3 - [(2-Animo-benzothiazole-6-sulfonyl) -isobutylamino] -1 -benzyl-2-hydroxypropyl} -carbamic acid benzyl ester; {(1S, 2R) -3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl) carbamic acid pyridin-3-ylmethyl ester; {(1S, 2R); 3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl) carbamic acid thiazol-5-ylmethyl ester; {(1S, 2R) -3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2- (2,6-dimethylphenoxy) acetamide; 3-Amino {(1S, 2R) -3 - [(2-amino-benzothiazol-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl) -2-methyl-benzamide; 4-amino - {(18,2R) -3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2-methylbenzamide; 5-amino-{(1S, 2R) -3 - [(2-aminomethylbenzotliazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2-methylbenzamidine; N - {(1S, 2R) -3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -2-methylbenzamide; N - {(1S, 2R) -3 - [(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -4-hydroxy-2-methyl-benzamide; N- {1S, 2R) -3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -3-hydroxy-2-methylbenzamide; and {(1S, 2R) -3 - [(2-Amino-benzothiazol-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid (S) - (tetrahydrofuran-3-yl) ester. 10. A compound accordingto R1 is hexahydrofuroL2,3-b] furanyi oroxazolyl. A compound according to the invention is hexahydiOfuro [2.3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, and L is a direct bond. 12. A compound hexidohydrofuro [2,3-b] fiiranyl, oxazolyl, thiazolyl, pyridinyl, or phenylyl substituted with one or moresubstitueras independently selected from C 1-4 alkyl, hydroxy, aroino, halogen, aminoC 1-4 alkyl and mono-or di (C 1-4 alkyl) amino; and L is -O-. 13. A copolymer according to Rih hexahydrofuro [2,3-b] furanyl, tetrahydrofuranyl. oxazolyl, or phenyl substituted with one or more substitutedindependently selected frorn C1_alkyl, hydroxy, amino, halogen, aminoCMalkyl and 012893 mono-or di (Cualkyl) amino: and L is C1.5alkaned.iy 1-0- whereby -O- is attached tothe nitrogen of the amide. 14. Ri is hexahydro-cyclobutanhydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or phenylonexyl substituted withone or more substitutents independently selected from hydroxy, amino, halogen, aminoCyalkyl and mono-or di (C14aIkyl) amino; and is -O-C1-alkanediyl is attached to the group. 15. A compound according to any one of R5 andRé is Cualkyl, 16. A compound according to any one of R2 to hydrogen is hydrogen; R3 isphenylmethyl; R4 is Cualkyl. 17. a 1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid hexahydro-furo [2,3-b] furan-3-yl ester; {1-Benzyl-3 - [(2-dimethylamino-benzothiazol-6-sulfonyl) -isobutyl-amino] -2-hydroxy-propyl} -carbamic acid hexahydro-furo [2,3-b] furan-3- N- {1-Benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -2- (2,6-dimethyl-phenoxy) -acetamide ; N- {3 - [(2-aminobenzothiazole-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} -3-fluoro-2-methylbenzamide; N- {3 - [(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (4-aminomethyl-2,6-dimethyl-phenoxy) -acetamide; {1-Benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole] -6-sulfonyl) -amino] -propyl} -carbamic acid thiazol-5-ylmethyl ester: 3-amino-N- { 1-Benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -propyl] -2-methyl-benzamide; {1-Benzyl-2-hydroxy-3- [isobutyl- (2-ethylamino-benzothiazol-6-sulfonyl) -amino] -propyl} -carbamic acid tetrahydro-furan-3-yl ester: N- {1-benzyl} 2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -ammo] -propyl} -3-hydroxy-2-methyl-benzamide; N- {3 - [(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-anrino] -1-benzyl-2-hydroxypropyl} -2- (4-iodo-2,6-dimethyl-phenoxy) -acetamide; 2- (4-Aminotnethyl-2,6-dimethyl-phenoxy) -N- (1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -propyl} - acetamide; 2- (4-amino-2,6-diinethyl-plienoxy) -N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl] N-{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzotylazole-6-sulfonyl) -amino] propyl} -4-bromo-2-methyl-benzamide; 5 {1-Benzyl-2-hydroxy-3- [isobutyl- (2-methylammobenzothiazole-6-sulfonyl) -amino] -propyl) -carbamic acid oxazol-5-ylmethyl ester; 4-amino-N - {1-benzyl-2-hydroxy-3 - [isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -propyl) -3-hydroxy-2-methyl-benzamide; knows which, or a stereoisomeric fonn thereof. 10 18. The compound having the formula {3 - [(2-aminobenzothiazol-6-sulfonyl) isobutylamino] -1-benzyl-2-hydroxypropyl} carbamic acid hexahydro-furo [2, 3-b] furan-3-yl ester; {1-Benzyl-2-hydoxy-3- [isobutyl- (2-methylamino-benzothiazol-6-sulfonyl) -amino] -15-propyl} -carbamic acid hexahydro-furo [2,3-b] furan-3-yl ester; {1-Benzyl-3 - [(2-dimethylamino-benzothiazol-6-sulfonyl) -isobutyl-amino] -2-hydroxy-propyl) -carbamic acid hexahydro- & [2,3-b] furan-3- yl ester, gold has known gold stereoisomeric forai thereof, 19. A product for use in a method for inhibiting mutant HIV protease in amammal infected with said mutant HIV protease, said product comprising 2-amino-benzothiazole, having the formula (I) as defined in any one of suede 1 to 8, gold a V-oxide, knows, stereoisomeric form, racemic mixture, prodrug, ester ormetabolite thereof.